ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1135_1139del (p.Arg378_Arg379insTer)

dbSNP: rs267608077
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074635 SCV000107835 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000129834 SCV000184650 pathogenic Hereditary cancer-predisposing syndrome 2019-02-23 criteria provided, single submitter clinical testing The c.1135_1139delAGAGA pathogenic mutation (also known as p.R379*), located in coding exon 4 of the MSH6 gene, results from a deletion of 5 nucleotides at nucleotide positions 1135 to 1139. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been previously identified in an individual diagnosed with Lynch syndrome (Kets CM et al. Br. J. Cancer. 2006 Dec 18;95(12): 1678-82) and in a patient with CMMRD (Tesch VK et al. Front Immunol. 2018 Jul;9:1506). It has also been reported in an individual with breast cancer at age 60, as well as endometrial and ovarian cancer at age 61, whose endometrial tumor showed loss of MSH2 on IHC (Frolova AI et al. Gynecol. Oncol. 2015 Apr;137:7-13). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000202120 SCV000211383 pathogenic not provided 2021-06-03 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Kets 2006, Frolova 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 17117178, 17453009, 25617771, 26681312, 26845104, 27064304, 28152038, 28452373, 26689913, 28514183, 30013564, 29625052)
University of Washington Department of Laboratory Medicine,University of Washington RCV000074635 SCV000266088 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000504011 SCV000595850 pathogenic Colorectal cancer, hereditary nonpolyposis, type 5 2016-08-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129834 SCV000685168 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing This variant deletes 5 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/250986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000629947 SCV000750903 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-08-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074635 SCV000917791 pathogenic Lynch syndrome 2018-12-26 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1135_1139delAGAGA (p.Arg379X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245726 control chromosomes (gnomAD). c.1135_1139delAGAGA has been reported in the literature in individuals affected with Breast cancer, Ovarian cancer, polyups, and cervical cancer (Frolova_2017, Kets_2006, Shirts_2015, Susswein_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202120 SCV001469563 pathogenic not provided 2019-09-25 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
CeGaT Center for Human Genetics Tuebingen RCV000202120 SCV001747257 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories,Mayo Clinic RCV000202120 SCV000257205 likely pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000202120 SCV001552841 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000202120 SCV001742958 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000202120 SCV001808057 pathogenic not provided no assertion criteria provided clinical testing

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